Recent work has shown that glycosaminoglycans (GAGs) are involved in the regulation of many physiological processes, including human development, viral invasion, neuronal growth, and cancer metastasis. Initial evidence also suggests that the physiological message sent by cells is largely determined by the sulfation pattern of these polysaccharides. Attempts to study this 'sulfation code'have been hindered by the difficulty in obtaining homogenously sulfated GAGs. Genetic and biochemical methods produce mixtures of products. Furthermore, no general or selective synthetic methods are available for the selective sulfation of polyol compounds. In this proposal, a plan to eliminate this obstacle is outlined. The major objectives of the following proposal are threefold: (1) To develop regioselective methods for the sulfation or sulfonylation of one alcohol in a polyol using oligopeptide-based catalysts with modified histidine residues;(2) to apply this sulfonyl transfer catalyst to the functionalization of sugars and the synthesis of sulfated sugars, aminoglycans, and deoxysaccharides;(3) to probe the biological significance of specific sulfation patterns of GAGs using a library of oligosaccharides derived from these sugar derivatives. The first step in this plan is to expand a technique to selectively acylate carbohydrates that the Miller group has recently developed to allow for the sulfation and sulfonylation of alcohols. Using rational design of (5-turn peptides with modified histidine residues, hydrogen-bonding interactions will be engineered between the peptide catalyst and the carbohydrate substrate to achieve the desired selectivity. Once a moderately selective catalyst has been identified, kinetics and NMR conformational analysis will be used to elucidate the origin of the selectivity and design improved catalysts. In this manner, a series of catalysts will be developed to selectively sulfate or sulfonylate each position of relevant monosaccharides. The sulfonylated products will be further transformed into amino- or deoxysugars, as well as other sugar derivatives. Using these techniques, a library of sugars will be synthesized and used to construct novel GAG analogs. Complex sugars containing negatively-charged sulfate groups, known as sulfated polysaccharides, have been implicated in the control of many physiological processes, including human development, viral invasion, neuronal growth, and the growth and spread of cancer. The pattern of negative charges in these complex sugars is thought to act as a regulatory code in the body. By developing a method to provide more efficient access to sulfated polysaccharides, this work will facilitate the understanding of this sulfation code.
